ARTICLES PUBLISHED ONLINE: 17 NOVEMBER 2013 | DOI: 10.1038/NCHEM.1797
The aromatic ene reaction Dawen Niu and Thomas R. Hoye* The ene reaction is a pericyclic process in which an alkene with an allylic hydrogen atom (the ene donor) reacts with a second unsaturated species (the enophile) to form a new product with a transposed p-bond. The aromatic ene reaction, in which the alkene component is embedded in an aromatic ring, has only been reported in a few (four) instances and has proceeded in low yield (≤6%). Here, we show efficient aromatic ene reactions in which a thermally generated aryne intermediate engages a pendant m-alkylarene substituent to produce a dearomatized isotoluene, itself another versatile but rare reactive intermediate. Our experiments were guided by computational studies that revealed structural features conducive to the aromatic ene process. We proceeded to identify a cascade comprising three reactions: (1) hexadehydroDiels–Alder (for aryne generation), (2) intramolecular aromatic ene and (3) bimolecular Alder ene. The power of this cascade is evident from the structural complexity of the final products, the considerable scope, and the overall efficiency of these multistage, reagent- and by-product-free, single-pot transformations. ne reactions1, which involve the attack of an alkene (the ene donor) by an unsaturated enophile (A¼B or A;B), are well known in organic chemistry2. In the process, an allylic hydrogen atom is transferred to the enophile and the alkene p-bond is transposed (that is, C1¼C2–C3–H þ A¼B to H–B–A–C1–C2¼C3). Aromatic ene reactions—those in which an arene bearing a benzylic C–H bond serves as the ene donor (see 1 to 2, Fig. 1a)—are extremely rare. The only (four) reported examples involve o-benzyne (3) itself as the enophile. Each proceeds in low yield (≤6%) and is presumed to follow the pathway shown in Fig. 1b (that is, 1 to 5 via 4)3,4. The competing formation of bimolecular [4þ2] Diels– Alder reaction products between o-benzyne (3, now acting as a dienophile) and toluene (the diene) perhaps has contributed to the fact that this fundamentally intriguing but rare type of ene reaction has remained unexplored and unexploited. Arynes are known to function as enophiles5. The earliest examples were sporadic and isolated in their nature, but recent studies have established synthetically useful ene reaction protocols involving arynes as the enophile (Fig. 2a,b). Lautens and colleagues have reported the wide scope of intramolecular ene reactions of (classically generated) benzyne derivatives like 7 (from 6) in which pendent alkenes cyclize efficiently to provide annelated products like 8 (refs 6, 7). We recently described the intramolecular ene reaction of aryne 10 to give 11 (ref. 8). Cheng and co-workers have demonstrated the generality of a bimolecular propargylic ene reaction between an aryne (for example, 3, generated from 12 by the method of Kobayashi9) and an alkyne (see 13) to give an allene (see 14)10. Lee and colleagues have recently reported the considerable scope of reactions like 10 to 11 as well as an intramolecular propargylic ene reaction (15 to 17 via 16)11. Arynes are also known to participate in hetera-ene reactions with a phenol8,12 or aniline13 derivative serving as the ene donor. Here, we show the first examples of efficient aromatic ene reactions. These were developed in the context of arynes like 19, which possess suitably disposed aromatic substituents bearing an m-alkyl substituent, and pass through isotoluene species like 20. Isotoluenes are reactive intermediates in their own right, for which we also report some unprecedented transformations.
a The minimal strucutural elements for an aromatic ene reaction:
E
Results and discussion Realization of the aromatic ene reaction has been elusive to date, presumably for two fundamental reasons. First, the energetics of
A B
Aromatic ene
Rearomatized
H
product(s)
B
reaction
H
Enophile
A
H
1
2 A substituted isotoluene
b The only reported aromatic ene reaction(s): –
CO2 +
N2
Heat PhMe
H 3
Aromatic ene
1
H
H
CH2
reaction
H
4 H 3
5 6% yield (and 3–6% for analogous product from PhEt, PhiPr, or 1,3,5-Me3Ph)
Figure 1 | Structural delineation and previous example of an aromatic ene reaction. a, The minimal structural elements for an aromatic ene reaction: a potent enophile and an arene bearing a benzylic C–H bond as an ene donor. This transformation is rare because it requires the energetically demanding formation of a dearomatized isotoluene species (see 2). b, The only reported aromatic ene reactions involve the use of the highly energetic o-benzyne (3) in the role of enophile, which engages one of the alkylbenzenes toluene (1), ethylbenzene, cumene or mesitylene as the ene donor. The intermediate isotoluene 4 was invoked to account for the formation of product 5. Yields are marginal in part because products arising from [4þ2] cycloaddition between 3 and the p-system in arene 1 are formed competitively.
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA. * e-mail: [email protected] NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
1
ARTICLES a
NATURE CHEMISTRY c
Reactions of arynes with alkene ene donors O
O
Reactions of arynes with arene ene donors ?
O
LDA
Br
DOI: 10.1038/NCHEM.1797
r.t.
–HBr H OMe
OMe
Me
H OMe
18 6
7
98%
8
HDDA O
O
O 97 ºC 22 h
TMS H
Heptane (HDDA)
TMS
Alder ene TMS
H
H
(fast)
H
O
O
O
19 9
b
11 83%
10
Aromatic ene
This work:
Reactions of arynes with alkyne ene donors
TfO
TMS
H
KF 18-crown-6 +
H
THF, r.t.
12
H
20
H
3
14 68%
13
Rearomatized products R=
Et R
R O TsN
90 ºC 6h CH3CN (HDDA)
O
Alder ene
O
TsN
O
TsN
(fast) H
H
Et
Et
Et 15
17 73%
16
Figure 2 | Arynes as enophiles reacting with various types of ene donor. a, An alkene (an Alder ene reaction)6–8. b, An alkyne (a propargylic ene reaction)10,11. c, An arene donor bearing a suitably disposed benzylic hydrogen atom (an aromatic ene reaction, this work).
dearomatization associated with the primary ene event (see 1 to 2) require that the enophile be of inherently high reactivity. Second, o-benzyne, the only known enophile capable of overcoming this barrier, displays competitive [4þ2] (Diels–Alder) reactivity toward the dienic character that is necessarily present in the requisite aromatic ring of the ene donor3,4,8. We felt that both of these challenges—the issues of inherent reactivity and selectivity— might be surmountable by the use of properly designed aryne intermediates accessible by the hexadehydro-Diels–Alder (HDDA) reaction. The HDDA reaction generates bicyclic benzyne derivatives merely by heating suitable triyne precursors (9 to 10 (Fig. 2a), 15 to 16 (Fig. 2b) and 18 to 19 (Fig. 2c)) and comprises a general and powerful strategy for accessing these reactive intermediates8,14. Importantly, the arynes are produced in the absence of external reagents. This feature affords them a longer lifetime and an accordingly greater opportunity for entering into transformations with relatively high activation energies. Thus, HDDA-derived arynes also comprise a valuable platform upon which to exploit relatively rare, if not unprecedented, types of reactivity (for example, Si–O bond insertion8, phenol ene reaction8, benzenoid Diels–Alder cycloaddition (26a to 28a8, Fig. 3c), C–H 2
bond insertion15, aryne fluorination/trifluoromethylation/trifluoromethylthiolation16 and dihydrogen transfer from alkanes17). Substrate design: the Diels–Alder versus aromatic ene dichotomy. In the course of considering potential aromatic ene substrates like 19 (Fig. 2c), we reasoned that it should be possible to bias the reaction outcome away from an intramolecular Diels–Alder and towards the aromatic ene event (that is, 19 to 20) by appropriate design of the tethered substrate. We used computational methods to investigate the inherent energetic differences of reactions between o-benzyne (3) and toluene (1) (Fig. 3a). In these studies, two competing modes of reactivity were examined, namely aromatic ene (to 4, Figs 1b and 3a) and bimolecular Diels–Alder [4þ2] cycloaddition (to 21a and 21b, Fig. 3a). Density functional theory (DFT, M062X18/6-31G(d)) was used first to evaluate the relative stability of the primary products (4 and 21a/b) vis-a`-vis the o-benzyne/toluene reactant pair. Both the aromatic ene (to 4) and Diels–Alder (to 21a/b) reactions were found to be quite exothermic (and to a similar degree), even though the toluene moiety is dearomatized in each of these three primary products. This largely reflects the loss of the high strain energy in an aryne (50 kcal mol21; refs 19, 20) and the net gain from the exchange
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY a
ARTICLES
DOI: 10.1038/NCHEM.1797
b
‡ Me
‡
n
‡ n
‡ ‡
Me
Me
H TS-4
TS-21a 17.7
18.6 Energies
H
13.2 (n = 2)
17.5
Energies
TS-21b
in
Aromatic
in
kcal mol
0
–1
TS-24 18.3 (n = 2)
TS-23
kcal mol
Diels–Alder
0
(D–A) ‡
ene ‡
–1
n o-benzyne (3) + toluene (1)
–43.2
–40.9 (n = 2)
–46.7 H
(n = 2) –45.5 Me
n
22
–47.5 n
Me
Me H
H H 4
ene
H
–83.8 21a
23
21b
H
Me
24
D–A
n
TS-23
vs
TS-24
ΔG TS
1
22.0
vs
45.6
= 23.6
2
13.2
vs
18.3
= 5.1
3
14.4
vs
13.0
= –1.4
25
c TMS
O
O
TMS
O CH2
O
TMS
O O
85 ºC 18 h
m
CHCl3
m
m
H R
R 26a–c
R
R
R vs.
27
28 85%
a
1
Me
–
b
0
Me
88%
–
c
0
H
–
83%
R
R 27a–c
m
28a–c D–A product
Aromatic ene product
Figure 3 | Competition between aromatic ene and aromatic Diels–Alder pathways. a, Computed (DFT) energetics of possibilities for the bimolecular reaction between toluene (1) and o-benzyne (3) leading to the aromatic ene product 4 (an isotoluene) versus the Diels–Alder adducts 21a and 21b. b, Computed energetics of the analogous competitions for the tethered substrates 22 leading to the intramolecular ene product 23 versus the [4þ2] adduct 24; the potential energy surface is portrayed for the case where n ¼ 2, and the comparative values of DGTS are tabulated in the inset. c, Experimental results for the series of related HDDA substrates 26a–c; the first and last give, exclusively, the Diels–Alder products 28a and 28c, whereas 26b gives only the aromatic ene product 27b.
of p- for s-bonds that accompanies both the ene and Diels–Alder modes of reaction of the arene ring. We then located transition structures for each of these competing reactions. A notable finding is that the activation energies (DG ‡) of the intermolecular aromatic ene and cycloaddition processes are very similar to one another (Fig. 3a). This is well in line with the reported ratios among the isolated products 5, 21a and 21b (6:2:5)3,4. These results validated the merit of DFT analysis in this setting. We then used the same DFT method to study three benzyne derivatives 22 (n ¼ 1, 2 and 3), each differing only in the length of the methylene chain joining the tolyl to the benzyne moieties (Fig. 3b). In a previous report we described the reaction of substrate 26a (Fig. 3c) to give the Diels–Alder product 28a (85% isolated yield) to the exclusion of any observable amount of ene product 27a (ref. 8). In view of that previous observation, it was reassuring to see that the computed relative transition structure energies for 22 (n ¼ 3), which has the same tether length as 26a, favours the intramolecular Diels–Alder pathway. Encouragingly, computation of either of the other substrates 22 (n ¼ 1 or 2) showed a decided preference for the ene rather than the Diels– Alder event. The computed activation barrier for the aromatic ene reaction was considerably lower for the case for n ¼ 2 than for n ¼ 1. In the meantime, we synthesized substrate 26b, which
contains a two-atom link, to learn if the aromatic ene pathway would be preferred for this structural motif. Indeed, heating triyne 26b produced only the aromatic ene-type product 27b (88% yield). We presumed that the initial intramolecular aromatic ene adduct cleanly rearomatized (see 23 to 25 in Fig. 3b and later discussion) under the reaction conditions. The complementary substrate 26c, which lacks methyl substitution on the pendent aryl ring and is, therefore, an impotent aromatic ene substrate, was then used to establish that a Diels–Alder cycloaddition is indeed feasible in this framework; product 28c was isolated in 83% yield. It is satisfying that computational study is capable of identifying the key structural attribute in the substrate—a two-atom linker between the aryne and trapping arene rings—that permits it to undergo efficient aromatic ene reaction. Scope of the HDDA//aromatic ene reaction. To recapitulate, this unique HDDA//aromatic ene process (Table 1, top) converts a triyne substrate like 29 (bearing a (meta-alkyl)aryl substituent, connected through a two-atom linker) via an aryne like 30 to an isotoluene intermediate like 31, which aromatizes to a final tricyclic product like 32. As with all HDDA-initiated reactions8, this transformation is simply thermally induced, can be performed in a variety of non-participating solvents, and does not
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
3
ARTICLES
NATURE CHEMISTRY
DOI: 10.1038/NCHEM.1797
Table 1 | Examples of the HDDA-initiated aromatic ene reaction.
X
X HDDA X
aromatic ene
H
X Rearomatization
Intra-molecular H
H
H Me
Me 29
30
31
OAr
32
OAr
Ar = 3,5-di-MePh CO2Me
O MeO2C
O
O
O
O
TsN
O O
O
O
PhN
MeO2C
32a DCB, 165 °C, 4.5 h 65%
32c
32b DCE, 125 °C, 20 h 86%
O
CHCl3, 65 °C, 20 h 90% (NMR yield)
O O
PhN
O O
PhN
O
PhN
32e
32d DCB, 165 °C, 3.5 h 81%
CHCl3, 120 °C, 18 h 85%
O
O
TBS
O
PhN
O
OTBS
N Br
32f CHCl3, 120 °C, 18 h 84%
32g CHCl3, 120 °C, 18 h 77%
O
O
88%
O
O
32j CHCl3, 95 °C, 36 h 90%
O
O
O
32i CHCl3, 120 °C, 18 h 73%
32h DCE, 120 °C, 18 h
O
NBoc
O
O
PhN
+
O
PhN
OMe 32k DCB, 165 °C, 3.5 h 85%
32l DCB, 165 °C, 3.5 h 69%
32m DCB, 165 °C, 3.5 h 55%
32n
32o DCE, 120 °C, 18 h 80% (1:2 ratio)
The dotted line in each structure shows the disconnection made possible by the HDDA reaction, and the bold bond in each indicates the C–C bond formed via the aromatic ene reaction.
require particularly stringent reaction conditions (for example, oxygen- or water-free). The broad scope of the process is demonstrated by the results summarized in Table 1. Several particular features can be observed. (1) Arynes with a variety of different electronic properties, as governed by the functional groups within the triyne tether (red), are effective enophiles (see 27b and 32a–e and j). (2) The linker (blue) between the aryne enophile and arene ene donor can incorporate carbon, nitrogen or oxygen atoms and can bear substitution (32h). (3) Substituents on the arene donor (for example, alkoxy (32k), silyloxy (32f ) or halide (32g)) are well-tolerated. (4) On the other hand, minimally substituted arenes are also effective (see 32i). (5) The arene donor is not restricted to benzenoid derivatives; efficient formation of the pyridine-containing product 32j bodes well for potential ene trapping by other heteroaromatics. (6) Secondary benzylic C–H bonds will participate in the ene transfer event, although at a slightly slower rate than that of a primary (see 1:2 ratio of products 32n:32o). (7) The ability to generate the reactive aryne intermediate in the absence of other reagents (that is, by thermal activation only) was key to the uncovering of this aromatic ene reaction. This final point was reinforced by the outcome of our attempt to use the Lautens strategy (see 6 to 7 in Fig. 2a) to effect 4
the aromatic ene trapping of the aryne 34 generated by baseinduced elimination of HBr from bromoarene 33 (Fig. 4a). The biaryl 35 was formed, but in only 2% yield. Products resulting from reduction (36)17 or amine trapping (37) of the intermediate aryne were predominantly formed. Mechanistic investigations of the aromatic ene reaction. We performed studies relating to the mechanism of the final rearomatization event (see 23 to 25 (Fig. 3b) and 31 to 32 (Table 1, top)). Thermal, suprafacial, unimolecular reorganization of isotoluene to toluene is symmetry-forbidden, and the antarafacial variant of this 1,3-sigmatropic rearrangement is geometrically unfavourable21, if not untenable. Thus, the 1,3hydrogen atom migration event typically requires catalysis22. We speculated that adventitious water might be acting as a proton shuttle to promote conversion of 31 to 32 in a fashion like that known for keto-enol tautomerization23. To test this idea, we heated triyne 38 in the presence of D2O (specifically, D2O-saturated chloroform). The dominant product, 32e-d1 (Fig. 4b), was monodeuterated (93% deuterium incorporation, see 1H NMR spectrum of 32e-d1 and Supplementary page 24 for analysis). A complementary experiment was performed in which the
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY
ARTICLES
DOI: 10.1038/NCHEM.1797
a Attempted trapping of the classically generated aryne 34 by an aromatic ene reaction O
O
Br
O
O
O
LiNiPr2
i
+
THF, r.t. OMe
OMe
OMe
OMe 34
33
Pr2N
+
35 2%
OMe 36 24%
37a/b 61% (a:b = 2:3)
c Stereospecificity
b Water mediates rearomatization of the isotoluene intermediate
O
O O
O
O
PhN H
Me
CHCl3 D2O
H DO
O
PhN
120 °C H
H D
38
39
H
32e-d1
D
D
Me D
38-d3
120 °C 18 h
O
O
O D
D D
O
O
41-d3
A single diastereomer (d.r. > 98:2)
D CDCl3
Me
Me
+
O
PhN
O
120 °C
D
DCE
O
O O
38-d3
Me
Me
D
O
PhN H
H2O
H HO
H
D Me
H
Me H
D
D 39-d3
32e-d2
Figure 4 | Studies giving insight into the importance of reaction conditions and the mechanism of the HDDA//aromatic ene reactions. a, Attempted aromatic ene reaction of the aryne 34 generated by elimination of HBr from the aryl bromide 33 shows an advantage of using the reagent-free conditions of the HDDA reaction as the method for aryne formation. b, A pair of complementary deuterium labelling experiments strongly implicate the intermediacy of isotoluene 39. c, The cis-addition of carbon and deuterium across the maleic anhydride p-bond (see Supplementary Information for a discussion of the 1 H NMR-based assignment of the structure 41-d3) provides strong mechanistic evidence for the concerted nature of the bimolecular (Alder) ene reaction.
trideuterated substrate 38-d3 was heated, this time in the presence of H2O. In this case, the dominant product was 32e-d2 (Fig. 4b; see 1 H NMR spectrum of 32e-d2 and Supplementary page 24), in which one of the three aromatic deuterium atoms in triyne 38-d3 has been lost. These results are best explained by a rearomatization process such as that portrayed in the isotoluene intermediate 39. We next reasoned that because the isotoluene intermediate 39 formed via the initial aromatic ene reaction was sufficiently long-lived to encounter water, it might be possible to trap this species in an even more productive manner with an added external enophile. Indeed, when a 1,2-dichloroethane solution of the trideuterated substrate 38-d3 was heated in the presence of maleic anhydride24 (Fig. 4c), adduct 41-d3 was formed. Moreover, the net cis-addition of carbon and deuterium across the enophile p-bond was stereospecific (see 1H NMR spectrum of 41-d3 and Supplementary page 56 for a discussion of the coupling constant and chemical shift analysis), providing evidence for a concerted ene reaction between maleic anhydride and 39-d3. Scope of the HDDA//aromatic ene//Alder ene cascade. The successful transformation of 38 to 41 via 39 (Fig. 4c) showed that it was possible to unite an additional (bimolecular) ene trapping reaction with the initial (unimolecular) aromatic ene reaction. This amounts to a HDDA//aromatic ene//Alder ene cascade (Table 2, top). This sequence is enabled because the isotoluene intermediate 39 is still endowed with a considerable portion of the potential energy embodied in the three alkyne units in the initial HDDA substrate 38. The scope of this threestage cascade process can be seen from the examples shown in Table 2, where several features can be observed. (1) A variety of
types of external enophiles can be used to trap the isotoluene intermediate, including electron-deficient alkenes (maleic anhydride and maleimides, red), a-dicarbonyl compounds (pyruvates, glyoxalate and N-methylisatin, blue) and an N-sulfonylimine (green). (2) The overall cascade process is tolerant of a large number of inherently reactive functional groups, including imide, anhydride, ketone, ester, halogen, alcohol, aldehyde and sulfonamide, which are present in the trapping enophiles and the newly formed products, therefore demonstrating a considerable degree of chemoselectivity. (3) The process is also compatible with a broad array of functionality in the aryne precursor; derivatives of isoindolone, phthalide, fluorenone and indane can all be produced in high yields. (4) The reaction can be conducted at relatively high substrate (triyne) concentrations (0.2–0.3 M), which speaks to the inherently fast nature of the aromatic ene trapping step. (5) Only 1.2–2 equiv. of external trapping enophiles were used, which suggests that the isotoluene intermediate has a relatively long lifetime and bodes well for application to convergent coupling synthesis strategies using complex triyne substrates and complex trapping enophiles. (6) Various steps in the cascade are stereoselective, as indicated by the production of a 4:1 ratio of diastereomers 42i and its epimer from the corresponding (chiral) triyne. Although we do not know the exact origin of this selectivity, relative asymmetric induction in this case can occur at either (or both) of two stages: the aromatic ene substrate 44 can cyclize to either of the diastereotopic re and si faces of its (two equivalent) ortho-carbon atoms, and the Alder enophile can approach the isotoluene intermediate 43 in either an endo or exo fashion.
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
5
ARTICLES
NATURE CHEMISTRY
DOI: 10.1038/NCHEM.1797
Table 2 | Examples of the HDDA//aromatic ene//Alder ene cascade. O O HDDA//aromatic ene Triyne
+
A=B (an enophile)
(see Table 1)
B
H
Me Me A
A 39
O PhN
40
O
O
O
H B
O
O
O O
O
PhN
O
O
PhN
O PhN
PhN
PhN
OH O
O
OH EtO2C
OH
EtO2C
N
O Ph
O
41 DCE, 120 °C, 18 h 2.0 equiv. 63% (+20% 32e)
N
O
42c DCE, 120 °C, 18 h 1.2 equiv. 85%
42b DCE, 120 °C, 18 h 1.5 equiv. 67%
42a DCE, 120 °C, 18 h 1.6 equiv. 66% (+22% 32e)
O
TMS
O
Ts Cl
42d DCE, 120 °C, 18 h 1.2 equiv. 77%
42e DCE, 120 °C, 18 h 2.0 equiv. 82% (+4% of 32e)
Me
Me
O O
O
NH
O
Me
3,5-Me2PhO
O
CF3
O
O PhN
MeO2C
H
O
MeO2C
OH
O
43
NH N Ph
O
42f DCB, 165 °C, 3.5 h 1.5 equiv. 72% (+18% of 32d)
OH EtO2C
Ts
N
Cl
CF3
42g DCE, 115 °C, 24 h 1.2 equiv. 84%
O
Me 42i DCE, 120 °C, 18 h 1.2 equiv. 76% (4:1 d.r.)
42h DCE, 80 °C, 18 h 2.0 equiv. 85%
Me O
H
X-ray structure of 42i (major diastereoisomer)
44
In products 41 and 42a–i the moieties in red, blue and green are derived from trapping agents with C¼C (red), C¼O (blue) and C¼N (green) enophilic p-bonds, respectively.
Conclusions In conclusion, by capitalizing on the reagent-free, aryne-generating HDDA reaction and taking guidance from computational chemistry, we have designed substrates that reveal the generality of a thus far rare and elusive type of ene reaction in which an arene bearing a benzylic C–H bond functions as the ene donor. We have shown that the isotoluenes generated by this HDDA-enabled ‘aromatic ene’ reaction can rearomatize either by net rearrangement or through interception by external enophiles. Thus, two complementary overall transformations have emerged. In the first, the isotoluene rearomatizes to provide polycyclic products such as 32a–o (Table 1) in a process explained by water-mediated proton shuttling. In the second, the reactive isotoluene is further engaged by an external enophile to give products of yet greater structural complexity (see 41 and 42a–i, Table 2). This ene-upon-ene cascade reaction involves the overall formation of four carbon–carbon bonds and three rings, requires no external reagents, and generates no by-products. The discovery of this efficient aromatic ene reaction further attests to the importance of a key feature of the HDDA cycloisomerization, namely, its ability to deliver aryne intermediates in the absence of the potentially interfering reagents that typically accompany aryne formation by classical methods25. Finally, this work 6
presages additional choreographed cascades that can exploit the high potential energy innate to alkynes. We are currently investigating such possibilities.
Methods Full experimental procedures for the preparation of all new compounds, complete spectroscopic characterization data (aromatic ene substrates and products) and a description of the computational protocols and results can be found in the Supplementary Information. General procedure for the HDDA//aromatic ene reaction. A solution of the triyne precursor in the indicated solvent (0.03 M) was placed in a vial closed with a Teflon-lined cap and heated at the temperature indicated under each structure of the corresponding product in Table 1 (external bath). The product was purified by chromatography on silica gel after the indicated time. General procedure for the HDDA//aromatic ene//Alder ene cascade. A solution of the triyne precursor in the indicated solvent (0.2–0.3 M) and the corresponding enophile was placed in a vial closed with a Teflon-lined cap and heated at the temperature indicated under each structure of the corresponding product in Table 2 (external bath). Unless otherwise noted, the product was purified by chromatography on silica gel after the indicated time.
Received 7 August 2013; accepted 11 October 2013; published online 17 November 2013
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY
ARTICLES
DOI: 10.1038/NCHEM.1797
References ¨ ber die Anlagerung von Maleinsa¨ure1. Alder, K., Pascher, F. & Schmitz, A. U anhydrid und Azodicarbonsa¨ure-ester an einfach ungesa¨ttigte Koh an einfach ungesa¨ttigte Kohlenwasserstoffe. Zur Kenntnis von Substitutionsvorga¨ngen in der Allyl-Stellung. Ber. Dtsch Chem. Ges. 76, 27 (1943). 2. Hoffman, H. M. R. The ene reaction. Angew. Chem. Int. Ed. 8, 556–577 (1969). 3. Brinkley, Y. J. & Friedman, L. Novel ene and insertion reactions of benzyne and alkylbenzenes. Tetrahedron Lett. 13, 4141–4142 (1972). 4. Tabushi, I., Yamada, H., Yoshida, Z. & Oda, R. Reactions of benzyne with substituted benzenes. Bull. Chem. Soc. Jpn. 50, 285–290 (1977). 5. Hoffmann, R. W. Dehydrobenzene and Cycloalkynes Vol. 118 (Organic Chemistry, A Series of Monographs, Academic, 1967). 6. Candito, D. A., Panteleev, J. & Lautens, M. Intramolecular aryne–ene reaction: synthetic and mechanistic studies. J. Am. Chem. Soc. 133, 14200–14203 (2011). 7. Candito, D. A., Dobrovolsky, D. & Lautens, M. Development of an intramolecular aryne ene reaction and application to the formal synthesis of (+)-crinine. J. Am. Chem. Soc. 134, 15572–15580 (2012). 8. Hoye, T. R., Baire, B., Niu, D., Willoughby, P. H. & Woods, B. P. The hexadehydro-Diels–Alder reaction. Nature 490, 208–212 (2012). 9. Himeshima, Y., Sonoda, T. & Kobayashi, H. Fluoride-induced 1,2-elimination of o-trimethylsilylphenyl triflate to benzyne under mild conditions. Chem. Lett. 12, 1211–1214 (1983). 10. Jayanth, T. T., Jeganmohan, M., Cheng, M., Chu, S. & Cheng, C. Ene reaction of arynes with alkynes. J. Am. Chem. Soc. 128, 2232–2233 (2006). 11. Karmakar, R., Mamidipalli, P., Yun, S. Y. & Lee, D. Alder–ene reactions of arynes. Org. Lett. 15, 1938–1941 (2013). 12. Truong, T. & Daugulis, O. Divergent reaction pathways for phenol arylation by arynes: synthesis of helicenes and 2-arylphenols. Chem. Sci. 4, 531–535 (2013). 13. Pirali, T., Zhang, F., Miller, A. H., Head, J. L., McAusland, D. & Greaney, M. F. Transition-metal-free direct arylation of anilines. Angew. Chem. Int. Ed. 51, 1006–1009 (2012). 14. Baire, B., Niu, D., Willoughby, P. H., Woods, B. P. & Hoye, T. R. Synthesis of complex benzenoids via the intermediate generation of o-benzynes through the hexadehydro-Diels–Alder reaction. Nature Protoc. 8, 501–508 (2013). 15. Yun, S. Y., Wang, K-P., Lee, N-K., Mamidipalli, P. & Lee, D. Alkane C–H activation by aryne intermediates with a silver catalyst. J. Am. Chem. Soc. 135, 4668–4671 (2013). 16. Wang, K-P., Yun, S. Y., Mamidipalli, P. & Lee, D. Unified approaches for fluorination, trifluoromethylation, and trifluoromethylthiolation of arynes. Chem. Sci. 4, 3205–3211 (2013).
17. Niu, D., Willoughby, P. H., Baire, B., Woods, B. P. & Hoye, T. R. Alkane desaturation via concerted double hydrogen atom transfer to benzyne. Nature 501, 531–534 (2013). 18. Zhao, Y. & Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 120, 215–241 (2008). 19. Ajaz, A. et al. Concerted vs. stepwise mechanisms in dehydro-Diels-Alder reactions. J. Org. Chem. 76, 9320–9328 (2011). 20. Jiao, H., Schleyer, P. V. R., Warmuth, R., Houk, K. N. & Beno, B. R. Theoretical studies of the structure, aromaticity, and magnetic properties of o-benzyne. Angew. Chem. Int. Ed. 36, 2761–2764 (1997). 21. Rey, M., Huber, U. A. & Dreiding, A. S. Formation of homofulvenes. Tetrahedron Lett. 32, 3583–3588 (1968). 22. Kopecky, K. R. & Lau, M. Thermal reaction between 5-methylene-1,3cyclohexadiene and styrene. J. Org. Chem. 43, 525–526 (1978). 23. Chiang, Y., Kresge, A. J., Santaballa, J. A. & Wirz, J. Ketonization of acetophenone enol in aqueous buffer solutions. Rate–equilibrium relations and mechanism of the ‘uncatalyzed’ reaction. J. Am. Chem. Soc. 110, 5506–5510 (1988). ¨ ber die Addition von Maleinsa¨ure–anhydrid 24. Alder, V. K. & Schmitz-Josten, R. U an Styrol. Liebigs Ann. Chem. 595, 1–37 (1955). 25. Kitamura, T. Synthetic methods for the generation and preparative application of benzyne. Aust. J. Chem. 63, 987–1001 (2010).
Acknowledgements D.N. was partially supported by a University of Minnesota Graduate School Doctoral Dissertation Fellowship. Financial support was provided by the National Institutes of Health (CA76497 and GM65597).
Author contributions D.N and T.R.H. designed the experiments, analysed the data and wrote the manuscript.
Additional information Supplementary information and chemical compound information are available in the online version of the paper. Reprints and permissions information is available online at www.nature.com/reprints. Correspondence and requests for materials should be addressed to T.R.H.
Competing financial interests The authors declare no competing financial interests.
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
7
The aromatic ene reaction Dawen Niu and Thomas R. Hoye* The ene reaction is a pericyclic process in which an alkene with an allylic hydrogen atom (the ene donor) reacts with a second unsaturated species (the enophile) to form a new product with a transposed p-bond. The aromatic ene reaction, in which the alkene component is embedded in an aromatic ring, has only been reported in a few (four) instances and has proceeded in low yield (≤6%). Here, we show efficient aromatic ene reactions in which a thermally generated aryne intermediate engages a pendant m-alkylarene substituent to produce a dearomatized isotoluene, itself another versatile but rare reactive intermediate. Our experiments were guided by computational studies that revealed structural features conducive to the aromatic ene process. We proceeded to identify a cascade comprising three reactions: (1) hexadehydroDiels–Alder (for aryne generation), (2) intramolecular aromatic ene and (3) bimolecular Alder ene. The power of this cascade is evident from the structural complexity of the final products, the considerable scope, and the overall efficiency of these multistage, reagent- and by-product-free, single-pot transformations. ne reactions1, which involve the attack of an alkene (the ene donor) by an unsaturated enophile (A¼B or A;B), are well known in organic chemistry2. In the process, an allylic hydrogen atom is transferred to the enophile and the alkene p-bond is transposed (that is, C1¼C2–C3–H þ A¼B to H–B–A–C1–C2¼C3). Aromatic ene reactions—those in which an arene bearing a benzylic C–H bond serves as the ene donor (see 1 to 2, Fig. 1a)—are extremely rare. The only (four) reported examples involve o-benzyne (3) itself as the enophile. Each proceeds in low yield (≤6%) and is presumed to follow the pathway shown in Fig. 1b (that is, 1 to 5 via 4)3,4. The competing formation of bimolecular [4þ2] Diels– Alder reaction products between o-benzyne (3, now acting as a dienophile) and toluene (the diene) perhaps has contributed to the fact that this fundamentally intriguing but rare type of ene reaction has remained unexplored and unexploited. Arynes are known to function as enophiles5. The earliest examples were sporadic and isolated in their nature, but recent studies have established synthetically useful ene reaction protocols involving arynes as the enophile (Fig. 2a,b). Lautens and colleagues have reported the wide scope of intramolecular ene reactions of (classically generated) benzyne derivatives like 7 (from 6) in which pendent alkenes cyclize efficiently to provide annelated products like 8 (refs 6, 7). We recently described the intramolecular ene reaction of aryne 10 to give 11 (ref. 8). Cheng and co-workers have demonstrated the generality of a bimolecular propargylic ene reaction between an aryne (for example, 3, generated from 12 by the method of Kobayashi9) and an alkyne (see 13) to give an allene (see 14)10. Lee and colleagues have recently reported the considerable scope of reactions like 10 to 11 as well as an intramolecular propargylic ene reaction (15 to 17 via 16)11. Arynes are also known to participate in hetera-ene reactions with a phenol8,12 or aniline13 derivative serving as the ene donor. Here, we show the first examples of efficient aromatic ene reactions. These were developed in the context of arynes like 19, which possess suitably disposed aromatic substituents bearing an m-alkyl substituent, and pass through isotoluene species like 20. Isotoluenes are reactive intermediates in their own right, for which we also report some unprecedented transformations.
a The minimal strucutural elements for an aromatic ene reaction:
E
Results and discussion Realization of the aromatic ene reaction has been elusive to date, presumably for two fundamental reasons. First, the energetics of
A B
Aromatic ene
Rearomatized
H
product(s)
B
reaction
H
Enophile
A
H
1
2 A substituted isotoluene
b The only reported aromatic ene reaction(s): –
CO2 +
N2
Heat PhMe
H 3
Aromatic ene
1
H
H
CH2
reaction
H
4 H 3
5 6% yield (and 3–6% for analogous product from PhEt, PhiPr, or 1,3,5-Me3Ph)
Figure 1 | Structural delineation and previous example of an aromatic ene reaction. a, The minimal structural elements for an aromatic ene reaction: a potent enophile and an arene bearing a benzylic C–H bond as an ene donor. This transformation is rare because it requires the energetically demanding formation of a dearomatized isotoluene species (see 2). b, The only reported aromatic ene reactions involve the use of the highly energetic o-benzyne (3) in the role of enophile, which engages one of the alkylbenzenes toluene (1), ethylbenzene, cumene or mesitylene as the ene donor. The intermediate isotoluene 4 was invoked to account for the formation of product 5. Yields are marginal in part because products arising from [4þ2] cycloaddition between 3 and the p-system in arene 1 are formed competitively.
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA. * e-mail: [email protected] NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
1
ARTICLES a
NATURE CHEMISTRY c
Reactions of arynes with alkene ene donors O
O
Reactions of arynes with arene ene donors ?
O
LDA
Br
DOI: 10.1038/NCHEM.1797
r.t.
–HBr H OMe
OMe
Me
H OMe
18 6
7
98%
8
HDDA O
O
O 97 ºC 22 h
TMS H
Heptane (HDDA)
TMS
Alder ene TMS
H
H
(fast)
H
O
O
O
19 9
b
11 83%
10
Aromatic ene
This work:
Reactions of arynes with alkyne ene donors
TfO
TMS
H
KF 18-crown-6 +
H
THF, r.t.
12
H
20
H
3
14 68%
13
Rearomatized products R=
Et R
R O TsN
90 ºC 6h CH3CN (HDDA)
O
Alder ene
O
TsN
O
TsN
(fast) H
H
Et
Et
Et 15
17 73%
16
Figure 2 | Arynes as enophiles reacting with various types of ene donor. a, An alkene (an Alder ene reaction)6–8. b, An alkyne (a propargylic ene reaction)10,11. c, An arene donor bearing a suitably disposed benzylic hydrogen atom (an aromatic ene reaction, this work).
dearomatization associated with the primary ene event (see 1 to 2) require that the enophile be of inherently high reactivity. Second, o-benzyne, the only known enophile capable of overcoming this barrier, displays competitive [4þ2] (Diels–Alder) reactivity toward the dienic character that is necessarily present in the requisite aromatic ring of the ene donor3,4,8. We felt that both of these challenges—the issues of inherent reactivity and selectivity— might be surmountable by the use of properly designed aryne intermediates accessible by the hexadehydro-Diels–Alder (HDDA) reaction. The HDDA reaction generates bicyclic benzyne derivatives merely by heating suitable triyne precursors (9 to 10 (Fig. 2a), 15 to 16 (Fig. 2b) and 18 to 19 (Fig. 2c)) and comprises a general and powerful strategy for accessing these reactive intermediates8,14. Importantly, the arynes are produced in the absence of external reagents. This feature affords them a longer lifetime and an accordingly greater opportunity for entering into transformations with relatively high activation energies. Thus, HDDA-derived arynes also comprise a valuable platform upon which to exploit relatively rare, if not unprecedented, types of reactivity (for example, Si–O bond insertion8, phenol ene reaction8, benzenoid Diels–Alder cycloaddition (26a to 28a8, Fig. 3c), C–H 2
bond insertion15, aryne fluorination/trifluoromethylation/trifluoromethylthiolation16 and dihydrogen transfer from alkanes17). Substrate design: the Diels–Alder versus aromatic ene dichotomy. In the course of considering potential aromatic ene substrates like 19 (Fig. 2c), we reasoned that it should be possible to bias the reaction outcome away from an intramolecular Diels–Alder and towards the aromatic ene event (that is, 19 to 20) by appropriate design of the tethered substrate. We used computational methods to investigate the inherent energetic differences of reactions between o-benzyne (3) and toluene (1) (Fig. 3a). In these studies, two competing modes of reactivity were examined, namely aromatic ene (to 4, Figs 1b and 3a) and bimolecular Diels–Alder [4þ2] cycloaddition (to 21a and 21b, Fig. 3a). Density functional theory (DFT, M062X18/6-31G(d)) was used first to evaluate the relative stability of the primary products (4 and 21a/b) vis-a`-vis the o-benzyne/toluene reactant pair. Both the aromatic ene (to 4) and Diels–Alder (to 21a/b) reactions were found to be quite exothermic (and to a similar degree), even though the toluene moiety is dearomatized in each of these three primary products. This largely reflects the loss of the high strain energy in an aryne (50 kcal mol21; refs 19, 20) and the net gain from the exchange
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY a
ARTICLES
DOI: 10.1038/NCHEM.1797
b
‡ Me
‡
n
‡ n
‡ ‡
Me
Me
H TS-4
TS-21a 17.7
18.6 Energies
H
13.2 (n = 2)
17.5
Energies
TS-21b
in
Aromatic
in
kcal mol
0
–1
TS-24 18.3 (n = 2)
TS-23
kcal mol
Diels–Alder
0
(D–A) ‡
ene ‡
–1
n o-benzyne (3) + toluene (1)
–43.2
–40.9 (n = 2)
–46.7 H
(n = 2) –45.5 Me
n
22
–47.5 n
Me
Me H
H H 4
ene
H
–83.8 21a
23
21b
H
Me
24
D–A
n
TS-23
vs
TS-24
ΔG TS
1
22.0
vs
45.6
= 23.6
2
13.2
vs
18.3
= 5.1
3
14.4
vs
13.0
= –1.4
25
c TMS
O
O
TMS
O CH2
O
TMS
O O
85 ºC 18 h
m
CHCl3
m
m
H R
R 26a–c
R
R
R vs.
27
28 85%
a
1
Me
–
b
0
Me
88%
–
c
0
H
–
83%
R
R 27a–c
m
28a–c D–A product
Aromatic ene product
Figure 3 | Competition between aromatic ene and aromatic Diels–Alder pathways. a, Computed (DFT) energetics of possibilities for the bimolecular reaction between toluene (1) and o-benzyne (3) leading to the aromatic ene product 4 (an isotoluene) versus the Diels–Alder adducts 21a and 21b. b, Computed energetics of the analogous competitions for the tethered substrates 22 leading to the intramolecular ene product 23 versus the [4þ2] adduct 24; the potential energy surface is portrayed for the case where n ¼ 2, and the comparative values of DGTS are tabulated in the inset. c, Experimental results for the series of related HDDA substrates 26a–c; the first and last give, exclusively, the Diels–Alder products 28a and 28c, whereas 26b gives only the aromatic ene product 27b.
of p- for s-bonds that accompanies both the ene and Diels–Alder modes of reaction of the arene ring. We then located transition structures for each of these competing reactions. A notable finding is that the activation energies (DG ‡) of the intermolecular aromatic ene and cycloaddition processes are very similar to one another (Fig. 3a). This is well in line with the reported ratios among the isolated products 5, 21a and 21b (6:2:5)3,4. These results validated the merit of DFT analysis in this setting. We then used the same DFT method to study three benzyne derivatives 22 (n ¼ 1, 2 and 3), each differing only in the length of the methylene chain joining the tolyl to the benzyne moieties (Fig. 3b). In a previous report we described the reaction of substrate 26a (Fig. 3c) to give the Diels–Alder product 28a (85% isolated yield) to the exclusion of any observable amount of ene product 27a (ref. 8). In view of that previous observation, it was reassuring to see that the computed relative transition structure energies for 22 (n ¼ 3), which has the same tether length as 26a, favours the intramolecular Diels–Alder pathway. Encouragingly, computation of either of the other substrates 22 (n ¼ 1 or 2) showed a decided preference for the ene rather than the Diels– Alder event. The computed activation barrier for the aromatic ene reaction was considerably lower for the case for n ¼ 2 than for n ¼ 1. In the meantime, we synthesized substrate 26b, which
contains a two-atom link, to learn if the aromatic ene pathway would be preferred for this structural motif. Indeed, heating triyne 26b produced only the aromatic ene-type product 27b (88% yield). We presumed that the initial intramolecular aromatic ene adduct cleanly rearomatized (see 23 to 25 in Fig. 3b and later discussion) under the reaction conditions. The complementary substrate 26c, which lacks methyl substitution on the pendent aryl ring and is, therefore, an impotent aromatic ene substrate, was then used to establish that a Diels–Alder cycloaddition is indeed feasible in this framework; product 28c was isolated in 83% yield. It is satisfying that computational study is capable of identifying the key structural attribute in the substrate—a two-atom linker between the aryne and trapping arene rings—that permits it to undergo efficient aromatic ene reaction. Scope of the HDDA//aromatic ene reaction. To recapitulate, this unique HDDA//aromatic ene process (Table 1, top) converts a triyne substrate like 29 (bearing a (meta-alkyl)aryl substituent, connected through a two-atom linker) via an aryne like 30 to an isotoluene intermediate like 31, which aromatizes to a final tricyclic product like 32. As with all HDDA-initiated reactions8, this transformation is simply thermally induced, can be performed in a variety of non-participating solvents, and does not
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
3
ARTICLES
NATURE CHEMISTRY
DOI: 10.1038/NCHEM.1797
Table 1 | Examples of the HDDA-initiated aromatic ene reaction.
X
X HDDA X
aromatic ene
H
X Rearomatization
Intra-molecular H
H
H Me
Me 29
30
31
OAr
32
OAr
Ar = 3,5-di-MePh CO2Me
O MeO2C
O
O
O
O
TsN
O O
O
O
PhN
MeO2C
32a DCB, 165 °C, 4.5 h 65%
32c
32b DCE, 125 °C, 20 h 86%
O
CHCl3, 65 °C, 20 h 90% (NMR yield)
O O
PhN
O O
PhN
O
PhN
32e
32d DCB, 165 °C, 3.5 h 81%
CHCl3, 120 °C, 18 h 85%
O
O
TBS
O
PhN
O
OTBS
N Br
32f CHCl3, 120 °C, 18 h 84%
32g CHCl3, 120 °C, 18 h 77%
O
O
88%
O
O
32j CHCl3, 95 °C, 36 h 90%
O
O
O
32i CHCl3, 120 °C, 18 h 73%
32h DCE, 120 °C, 18 h
O
NBoc
O
O
PhN
+
O
PhN
OMe 32k DCB, 165 °C, 3.5 h 85%
32l DCB, 165 °C, 3.5 h 69%
32m DCB, 165 °C, 3.5 h 55%
32n
32o DCE, 120 °C, 18 h 80% (1:2 ratio)
The dotted line in each structure shows the disconnection made possible by the HDDA reaction, and the bold bond in each indicates the C–C bond formed via the aromatic ene reaction.
require particularly stringent reaction conditions (for example, oxygen- or water-free). The broad scope of the process is demonstrated by the results summarized in Table 1. Several particular features can be observed. (1) Arynes with a variety of different electronic properties, as governed by the functional groups within the triyne tether (red), are effective enophiles (see 27b and 32a–e and j). (2) The linker (blue) between the aryne enophile and arene ene donor can incorporate carbon, nitrogen or oxygen atoms and can bear substitution (32h). (3) Substituents on the arene donor (for example, alkoxy (32k), silyloxy (32f ) or halide (32g)) are well-tolerated. (4) On the other hand, minimally substituted arenes are also effective (see 32i). (5) The arene donor is not restricted to benzenoid derivatives; efficient formation of the pyridine-containing product 32j bodes well for potential ene trapping by other heteroaromatics. (6) Secondary benzylic C–H bonds will participate in the ene transfer event, although at a slightly slower rate than that of a primary (see 1:2 ratio of products 32n:32o). (7) The ability to generate the reactive aryne intermediate in the absence of other reagents (that is, by thermal activation only) was key to the uncovering of this aromatic ene reaction. This final point was reinforced by the outcome of our attempt to use the Lautens strategy (see 6 to 7 in Fig. 2a) to effect 4
the aromatic ene trapping of the aryne 34 generated by baseinduced elimination of HBr from bromoarene 33 (Fig. 4a). The biaryl 35 was formed, but in only 2% yield. Products resulting from reduction (36)17 or amine trapping (37) of the intermediate aryne were predominantly formed. Mechanistic investigations of the aromatic ene reaction. We performed studies relating to the mechanism of the final rearomatization event (see 23 to 25 (Fig. 3b) and 31 to 32 (Table 1, top)). Thermal, suprafacial, unimolecular reorganization of isotoluene to toluene is symmetry-forbidden, and the antarafacial variant of this 1,3-sigmatropic rearrangement is geometrically unfavourable21, if not untenable. Thus, the 1,3hydrogen atom migration event typically requires catalysis22. We speculated that adventitious water might be acting as a proton shuttle to promote conversion of 31 to 32 in a fashion like that known for keto-enol tautomerization23. To test this idea, we heated triyne 38 in the presence of D2O (specifically, D2O-saturated chloroform). The dominant product, 32e-d1 (Fig. 4b), was monodeuterated (93% deuterium incorporation, see 1H NMR spectrum of 32e-d1 and Supplementary page 24 for analysis). A complementary experiment was performed in which the
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY
ARTICLES
DOI: 10.1038/NCHEM.1797
a Attempted trapping of the classically generated aryne 34 by an aromatic ene reaction O
O
Br
O
O
O
LiNiPr2
i
+
THF, r.t. OMe
OMe
OMe
OMe 34
33
Pr2N
+
35 2%
OMe 36 24%
37a/b 61% (a:b = 2:3)
c Stereospecificity
b Water mediates rearomatization of the isotoluene intermediate
O
O O
O
O
PhN H
Me
CHCl3 D2O
H DO
O
PhN
120 °C H
H D
38
39
H
32e-d1
D
D
Me D
38-d3
120 °C 18 h
O
O
O D
D D
O
O
41-d3
A single diastereomer (d.r. > 98:2)
D CDCl3
Me
Me
+
O
PhN
O
120 °C
D
DCE
O
O O
38-d3
Me
Me
D
O
PhN H
H2O
H HO
H
D Me
H
Me H
D
D 39-d3
32e-d2
Figure 4 | Studies giving insight into the importance of reaction conditions and the mechanism of the HDDA//aromatic ene reactions. a, Attempted aromatic ene reaction of the aryne 34 generated by elimination of HBr from the aryl bromide 33 shows an advantage of using the reagent-free conditions of the HDDA reaction as the method for aryne formation. b, A pair of complementary deuterium labelling experiments strongly implicate the intermediacy of isotoluene 39. c, The cis-addition of carbon and deuterium across the maleic anhydride p-bond (see Supplementary Information for a discussion of the 1 H NMR-based assignment of the structure 41-d3) provides strong mechanistic evidence for the concerted nature of the bimolecular (Alder) ene reaction.
trideuterated substrate 38-d3 was heated, this time in the presence of H2O. In this case, the dominant product was 32e-d2 (Fig. 4b; see 1 H NMR spectrum of 32e-d2 and Supplementary page 24), in which one of the three aromatic deuterium atoms in triyne 38-d3 has been lost. These results are best explained by a rearomatization process such as that portrayed in the isotoluene intermediate 39. We next reasoned that because the isotoluene intermediate 39 formed via the initial aromatic ene reaction was sufficiently long-lived to encounter water, it might be possible to trap this species in an even more productive manner with an added external enophile. Indeed, when a 1,2-dichloroethane solution of the trideuterated substrate 38-d3 was heated in the presence of maleic anhydride24 (Fig. 4c), adduct 41-d3 was formed. Moreover, the net cis-addition of carbon and deuterium across the enophile p-bond was stereospecific (see 1H NMR spectrum of 41-d3 and Supplementary page 56 for a discussion of the coupling constant and chemical shift analysis), providing evidence for a concerted ene reaction between maleic anhydride and 39-d3. Scope of the HDDA//aromatic ene//Alder ene cascade. The successful transformation of 38 to 41 via 39 (Fig. 4c) showed that it was possible to unite an additional (bimolecular) ene trapping reaction with the initial (unimolecular) aromatic ene reaction. This amounts to a HDDA//aromatic ene//Alder ene cascade (Table 2, top). This sequence is enabled because the isotoluene intermediate 39 is still endowed with a considerable portion of the potential energy embodied in the three alkyne units in the initial HDDA substrate 38. The scope of this threestage cascade process can be seen from the examples shown in Table 2, where several features can be observed. (1) A variety of
types of external enophiles can be used to trap the isotoluene intermediate, including electron-deficient alkenes (maleic anhydride and maleimides, red), a-dicarbonyl compounds (pyruvates, glyoxalate and N-methylisatin, blue) and an N-sulfonylimine (green). (2) The overall cascade process is tolerant of a large number of inherently reactive functional groups, including imide, anhydride, ketone, ester, halogen, alcohol, aldehyde and sulfonamide, which are present in the trapping enophiles and the newly formed products, therefore demonstrating a considerable degree of chemoselectivity. (3) The process is also compatible with a broad array of functionality in the aryne precursor; derivatives of isoindolone, phthalide, fluorenone and indane can all be produced in high yields. (4) The reaction can be conducted at relatively high substrate (triyne) concentrations (0.2–0.3 M), which speaks to the inherently fast nature of the aromatic ene trapping step. (5) Only 1.2–2 equiv. of external trapping enophiles were used, which suggests that the isotoluene intermediate has a relatively long lifetime and bodes well for application to convergent coupling synthesis strategies using complex triyne substrates and complex trapping enophiles. (6) Various steps in the cascade are stereoselective, as indicated by the production of a 4:1 ratio of diastereomers 42i and its epimer from the corresponding (chiral) triyne. Although we do not know the exact origin of this selectivity, relative asymmetric induction in this case can occur at either (or both) of two stages: the aromatic ene substrate 44 can cyclize to either of the diastereotopic re and si faces of its (two equivalent) ortho-carbon atoms, and the Alder enophile can approach the isotoluene intermediate 43 in either an endo or exo fashion.
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
5
ARTICLES
NATURE CHEMISTRY
DOI: 10.1038/NCHEM.1797
Table 2 | Examples of the HDDA//aromatic ene//Alder ene cascade. O O HDDA//aromatic ene Triyne
+
A=B (an enophile)
(see Table 1)
B
H
Me Me A
A 39
O PhN
40
O
O
O
H B
O
O
O O
O
PhN
O
O
PhN
O PhN
PhN
PhN
OH O
O
OH EtO2C
OH
EtO2C
N
O Ph
O
41 DCE, 120 °C, 18 h 2.0 equiv. 63% (+20% 32e)
N
O
42c DCE, 120 °C, 18 h 1.2 equiv. 85%
42b DCE, 120 °C, 18 h 1.5 equiv. 67%
42a DCE, 120 °C, 18 h 1.6 equiv. 66% (+22% 32e)
O
TMS
O
Ts Cl
42d DCE, 120 °C, 18 h 1.2 equiv. 77%
42e DCE, 120 °C, 18 h 2.0 equiv. 82% (+4% of 32e)
Me
Me
O O
O
NH
O
Me
3,5-Me2PhO
O
CF3
O
O PhN
MeO2C
H
O
MeO2C
OH
O
43
NH N Ph
O
42f DCB, 165 °C, 3.5 h 1.5 equiv. 72% (+18% of 32d)
OH EtO2C
Ts
N
Cl
CF3
42g DCE, 115 °C, 24 h 1.2 equiv. 84%
O
Me 42i DCE, 120 °C, 18 h 1.2 equiv. 76% (4:1 d.r.)
42h DCE, 80 °C, 18 h 2.0 equiv. 85%
Me O
H
X-ray structure of 42i (major diastereoisomer)
44
In products 41 and 42a–i the moieties in red, blue and green are derived from trapping agents with C¼C (red), C¼O (blue) and C¼N (green) enophilic p-bonds, respectively.
Conclusions In conclusion, by capitalizing on the reagent-free, aryne-generating HDDA reaction and taking guidance from computational chemistry, we have designed substrates that reveal the generality of a thus far rare and elusive type of ene reaction in which an arene bearing a benzylic C–H bond functions as the ene donor. We have shown that the isotoluenes generated by this HDDA-enabled ‘aromatic ene’ reaction can rearomatize either by net rearrangement or through interception by external enophiles. Thus, two complementary overall transformations have emerged. In the first, the isotoluene rearomatizes to provide polycyclic products such as 32a–o (Table 1) in a process explained by water-mediated proton shuttling. In the second, the reactive isotoluene is further engaged by an external enophile to give products of yet greater structural complexity (see 41 and 42a–i, Table 2). This ene-upon-ene cascade reaction involves the overall formation of four carbon–carbon bonds and three rings, requires no external reagents, and generates no by-products. The discovery of this efficient aromatic ene reaction further attests to the importance of a key feature of the HDDA cycloisomerization, namely, its ability to deliver aryne intermediates in the absence of the potentially interfering reagents that typically accompany aryne formation by classical methods25. Finally, this work 6
presages additional choreographed cascades that can exploit the high potential energy innate to alkynes. We are currently investigating such possibilities.
Methods Full experimental procedures for the preparation of all new compounds, complete spectroscopic characterization data (aromatic ene substrates and products) and a description of the computational protocols and results can be found in the Supplementary Information. General procedure for the HDDA//aromatic ene reaction. A solution of the triyne precursor in the indicated solvent (0.03 M) was placed in a vial closed with a Teflon-lined cap and heated at the temperature indicated under each structure of the corresponding product in Table 1 (external bath). The product was purified by chromatography on silica gel after the indicated time. General procedure for the HDDA//aromatic ene//Alder ene cascade. A solution of the triyne precursor in the indicated solvent (0.2–0.3 M) and the corresponding enophile was placed in a vial closed with a Teflon-lined cap and heated at the temperature indicated under each structure of the corresponding product in Table 2 (external bath). Unless otherwise noted, the product was purified by chromatography on silica gel after the indicated time.
Received 7 August 2013; accepted 11 October 2013; published online 17 November 2013
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY
ARTICLES
DOI: 10.1038/NCHEM.1797
References ¨ ber die Anlagerung von Maleinsa¨ure1. Alder, K., Pascher, F. & Schmitz, A. U anhydrid und Azodicarbonsa¨ure-ester an einfach ungesa¨ttigte Koh an einfach ungesa¨ttigte Kohlenwasserstoffe. Zur Kenntnis von Substitutionsvorga¨ngen in der Allyl-Stellung. Ber. Dtsch Chem. Ges. 76, 27 (1943). 2. Hoffman, H. M. R. The ene reaction. Angew. Chem. Int. Ed. 8, 556–577 (1969). 3. Brinkley, Y. J. & Friedman, L. Novel ene and insertion reactions of benzyne and alkylbenzenes. Tetrahedron Lett. 13, 4141–4142 (1972). 4. Tabushi, I., Yamada, H., Yoshida, Z. & Oda, R. Reactions of benzyne with substituted benzenes. Bull. Chem. Soc. Jpn. 50, 285–290 (1977). 5. Hoffmann, R. W. Dehydrobenzene and Cycloalkynes Vol. 118 (Organic Chemistry, A Series of Monographs, Academic, 1967). 6. Candito, D. A., Panteleev, J. & Lautens, M. Intramolecular aryne–ene reaction: synthetic and mechanistic studies. J. Am. Chem. Soc. 133, 14200–14203 (2011). 7. Candito, D. A., Dobrovolsky, D. & Lautens, M. Development of an intramolecular aryne ene reaction and application to the formal synthesis of (+)-crinine. J. Am. Chem. Soc. 134, 15572–15580 (2012). 8. Hoye, T. R., Baire, B., Niu, D., Willoughby, P. H. & Woods, B. P. The hexadehydro-Diels–Alder reaction. Nature 490, 208–212 (2012). 9. Himeshima, Y., Sonoda, T. & Kobayashi, H. Fluoride-induced 1,2-elimination of o-trimethylsilylphenyl triflate to benzyne under mild conditions. Chem. Lett. 12, 1211–1214 (1983). 10. Jayanth, T. T., Jeganmohan, M., Cheng, M., Chu, S. & Cheng, C. Ene reaction of arynes with alkynes. J. Am. Chem. Soc. 128, 2232–2233 (2006). 11. Karmakar, R., Mamidipalli, P., Yun, S. Y. & Lee, D. Alder–ene reactions of arynes. Org. Lett. 15, 1938–1941 (2013). 12. Truong, T. & Daugulis, O. Divergent reaction pathways for phenol arylation by arynes: synthesis of helicenes and 2-arylphenols. Chem. Sci. 4, 531–535 (2013). 13. Pirali, T., Zhang, F., Miller, A. H., Head, J. L., McAusland, D. & Greaney, M. F. Transition-metal-free direct arylation of anilines. Angew. Chem. Int. Ed. 51, 1006–1009 (2012). 14. Baire, B., Niu, D., Willoughby, P. H., Woods, B. P. & Hoye, T. R. Synthesis of complex benzenoids via the intermediate generation of o-benzynes through the hexadehydro-Diels–Alder reaction. Nature Protoc. 8, 501–508 (2013). 15. Yun, S. Y., Wang, K-P., Lee, N-K., Mamidipalli, P. & Lee, D. Alkane C–H activation by aryne intermediates with a silver catalyst. J. Am. Chem. Soc. 135, 4668–4671 (2013). 16. Wang, K-P., Yun, S. Y., Mamidipalli, P. & Lee, D. Unified approaches for fluorination, trifluoromethylation, and trifluoromethylthiolation of arynes. Chem. Sci. 4, 3205–3211 (2013).
17. Niu, D., Willoughby, P. H., Baire, B., Woods, B. P. & Hoye, T. R. Alkane desaturation via concerted double hydrogen atom transfer to benzyne. Nature 501, 531–534 (2013). 18. Zhao, Y. & Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 120, 215–241 (2008). 19. Ajaz, A. et al. Concerted vs. stepwise mechanisms in dehydro-Diels-Alder reactions. J. Org. Chem. 76, 9320–9328 (2011). 20. Jiao, H., Schleyer, P. V. R., Warmuth, R., Houk, K. N. & Beno, B. R. Theoretical studies of the structure, aromaticity, and magnetic properties of o-benzyne. Angew. Chem. Int. Ed. 36, 2761–2764 (1997). 21. Rey, M., Huber, U. A. & Dreiding, A. S. Formation of homofulvenes. Tetrahedron Lett. 32, 3583–3588 (1968). 22. Kopecky, K. R. & Lau, M. Thermal reaction between 5-methylene-1,3cyclohexadiene and styrene. J. Org. Chem. 43, 525–526 (1978). 23. Chiang, Y., Kresge, A. J., Santaballa, J. A. & Wirz, J. Ketonization of acetophenone enol in aqueous buffer solutions. Rate–equilibrium relations and mechanism of the ‘uncatalyzed’ reaction. J. Am. Chem. Soc. 110, 5506–5510 (1988). ¨ ber die Addition von Maleinsa¨ure–anhydrid 24. Alder, V. K. & Schmitz-Josten, R. U an Styrol. Liebigs Ann. Chem. 595, 1–37 (1955). 25. Kitamura, T. Synthetic methods for the generation and preparative application of benzyne. Aust. J. Chem. 63, 987–1001 (2010).
Acknowledgements D.N. was partially supported by a University of Minnesota Graduate School Doctoral Dissertation Fellowship. Financial support was provided by the National Institutes of Health (CA76497 and GM65597).
Author contributions D.N and T.R.H. designed the experiments, analysed the data and wrote the manuscript.
Additional information Supplementary information and chemical compound information are available in the online version of the paper. Reprints and permissions information is available online at www.nature.com/reprints. Correspondence and requests for materials should be addressed to T.R.H.
Competing financial interests The authors declare no competing financial interests.
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
7
